The Oligodendrocyte Transcription Factor 2 OLIG2 regulates transcriptional repression during myelinogenesis in rodents

Abstract

OLIG2 is a transcription factor that activates the expression of myelin-associated genes in the oligodendrocyte-lineage cells. However, the mechanisms of myelin gene inactivation are unclear. Here, we uncover a non-canonical function of OLIG2 in transcriptional repression to modulate myelinogenesis by functionally interacting with tri-methyltransferase SETDB1. Immunoprecipitation and chromatin-immunoprecipitation assays show that OLIG2 recruits SETDB1 for H3K9me3 modification on the Sox11 gene, which leads to the inhibition of Sox11 expression during the differentiation of oligodendrocytes progenitor cells (OPCs) into immature oligodendrocytes (iOLs). Tissue-specific depletion of Setdb1 in mice results in the hypomyelination during development and remyelination defects in the injured rodents. Knockdown of Sox11 by siRNA in rat primary OPCs or depletion of Sox11 in the oligodendrocyte lineage in mice could rescue the hypomyelination phenotype caused by the loss of OLIG2. In summary, our work demonstrates that the OLIG2-SETDB1 complex can mediate transcriptional repression in OPCs, affecting myelination.

Brain injuries and complex motor learning suppress Olig2 in a subpopulation of oligodendrocyte precursor cells

“…In addition, as seen in zebrafish optic tectum, a subtype of OPCs remain precursors throughout life and control axonal remodeling, never differentiating into myelinating oligodendrocytes (Xiao et al, 2022). A recent study has demonstrated that a set of genes, involved in pathways including neuronal differentiation and brain development, are repressed by Olig2 to ensure OPC differentiation into oligodendrocytes (K. Zhang et al, 2022). Therefore, it is tempting to speculate that OPCs switch off Olig2 expression and remain as precursors or NG2 glia upon the change of brain activity.…”

Single-cell triple-omics uncovers DNA methylation as key feature of stemness in the healthy and ischemic adult brain

“…Zhou et al, 2015). Regions lowly demethylated in oligodendrocytes were enriched for the motif of Olig2, a wellstudied master regulator of oligodendrocyte cell identity (K. Zhang et al, 2022;Q. Zhou et al, 2000), as well as Tcf12, which may be involved in the known generation of oligodendrocyte-fated NSCs by Wnt ligands (Ortega et al, 2013).…”

“…Zhou et al, 2015). Regions lowly demethylated in oligodendrocytes were enriched for the motif of Olig2, a well-studied master regulator of oligodendrocyte cell identity (K. Zhang et al, 2022; Q.…”

“…To our surprise, however, we detected active demethylation in hundreds of oligodendrocyte LMRs. Nearby genes include Sox10, a transcription factor that acts as a master regulator of oligodendrocyte fate (Mokhtarzadeh Khanghahi et al, 2018; Pozniak et al, 2010; K. Zhang et al, 2022), and myelin basic protein (Mbp) (Fig.…”

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

“…The effect can be reversed by using a physiological antagonist of BMP4, such as noggin, which may restore differentiation [ 91 , 106 , 107 ]. OLIG2 appears to interact with a variety of factors, such as ASCL1, BRG1, transcription factor 4 (TCF4), and SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to ensure proper OPCs differentiation [ 108 , 109 , 110 , 111 , 112 ]. G protein-coupled receptor 17 (GPR17) can act as a downregulator of OLIG1 that negatively controls the maturation and coordinates the generation of myelinating OLs from pre-myelinating OLs through ID proteins [ 113 ].…”